The present invention generally relates to a serial of boraadamantane compounds and their potential biological activities against pathogenic viruses as well as other medical applications. More particularly, these boraadamantane compounds which have general chemical structures shown in FIG. 1 are the pharmaceutical agents. The pathogenic viruses are Hepatitis C viruses, and Influenza A and B. Other medical applications include usage as dopamine agonists for the treatment of Parkinson""s disease.
Hepatitis C infection is associated with advanced liver disease (Liang, et al. Hepatology 18:1326-1333, (1993) and Tsukuma, et. al. The New England Journal of Medicine 328:1797-1801 (1993)), and liver failure due to hepatitis C infection is the most common indication for liver transplantation. Currently, the approved treatment for hepatitis C infection is xcex1-interferon with or without combination of another pharmaceutical agents, e.g. ribavirin. However, many of those responding to these treatments will relapse upon discontinuation of the therapies (Davis, et al. The New England Journal of Medicine 321:1501-1506 (1989) and Di Bisceglie, et al. The New England Journal of Medicine 321:1506-1510 (1989)). Most of the patients who are retreated will again relapse if these drugs were withdrawed (Tine et al. Journal of Hepatology 13:192-199 (1991)). For those patients who do not respond to the initial interferon therapies, heavier dose treatments only produced little positive results. Significant increase of side effects has been observed on those patients treated with high dose regiments (Poynard et al. New England Journal of Medicine 332:1457-1462 (1995)). The low response rate and significant positive synergistic effect of combination of xcex1-interferon with other pharmaceutical agent such as ribavirin have prompt investigators to search for other drugs which may be active against hepatitis C virus.
Smith J P (Digestive Diseases Sciences 1997 August; 42(8):1681-7) of Pennsylvania State University performed an open-labeled prospective pilot study to test the safety and efficacy of the antiviral drug, amantadine, in patients with chronic hepatitis C infection who had previously failed therapy with interferon-alpha 2b. Their clinical results indicated that amantadine improved both biochemical and virological markers in patients with hepatitis C who had previously not responded to treatment with interferon.
Brillanti S et al. (Italian Journal of Gastroentoerology and Hepatology 1999 March; 31(2):130-4) reported their pilot study evaluating the potential efficacy and safety of triple antiviral therapy in xcex1-interferon non-responders. Patients with chronic hepatitis C who had failed to respond to a 6 month course of xcex1-interferon were randomly assigned to receive two different types of therapies (double therapy or triple therapy) for 6 months. Double therapy: combination of xcex1-interferon+oral ribavirin. Triple therapy: same combination+oral amantadine (1-adamantanamine hydrochloride; Symmetrel; see chemical structure in FIG. 2). The clinical results indicated that: Triple therapy seems to be able to induce biochemical and virological responses significant better than the double therapy. Triple therapy also sustained these antiviral responses longer than the double therapy.
Amantadine Hydrochloride, N. F. (Orth R. E. in xe2x80x9cPrincipels of Medicinal Chemistry, 2nd edition, page 866-867. Ed. Foye, W. O. (1981)) has been approved by the FDA for the treatment of influenza A2 infection. It is active against influenza A, A1 and A2, Sendai and rubella viruses. Amantadine (Neumeyer J. L. in Principles of Medicinal Chemistry, 2nd edition, page 248-249. Ed. Foye W. O. (1981)) also has clinically significant anti-parkinsonian effects. It appears to increase the release of dopamine and enhance accumulation of brain dopamine with fewer side effects than levodopa or the anticholinergic drugs.
Langmuir (Mathison I. W. et al. in Principles of Medicinal Chemistry 2nd Edition, page 79-88. Ed. Foy W. O. (1981)) originated the concept of chemical isosterism. He elaborated upon the similarities in physicochemical properties of atoms, groups, radicals and molecules with similar electronic structures. Table 1 is a comparison of the physical properties of N2O and CO2 and illustrates some of the data compiled by Langmuir; similar relationships have been shown for N2 and CO. Hinsberg first proposed the isosteric replacement of CHxe2x95x90CH by S and recognized the interchanging of the various aromatic rings, such as thiophene, benzene, pyridine, pyrrole and furan as isosteric group replacements.
Chemical isosterism when applied in the drug design and molecular modification in the creation of new and improved therapeutic agents was termed xe2x80x9cbioisosterismxe2x80x9d by Friedman. The classic monovalent bioisostereomers included the halogens and the groups xe2x80x94XHn, where X is C, N, O, and S; n=1 to 3. The divalent atoms and groups are Rxe2x80x94Oxe2x80x94Rxe2x80x2, Rxe2x80x94NHxe2x80x94Rxe2x80x2, Rxe2x80x94CH2xe2x80x94Rxe2x80x2 and Rxe2x80x94SiH2xe2x80x94Rxe2x80x2. The trivalent bioisosteres include Rxe2x80x94Nxe2x95x90Rxe2x80x2 and Rxe2x80x94CHxe2x95x90Rxe2x80x2. Tetrsubstituted atoms are: xe2x95x90Cxe2x95x90, xe2x95x90N+xe2x95x90, and xe2x95x90P+xe2x95x90. The group relating to ring equivalents includes the interchange of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NH, and xe2x80x94CH2xe2x80x94.
FIGS. 3 and 4 show examples of bioisosteric applications in pharmaceutical agents. For example, both phenylephrine and alkylsulfonamidophenethanolamine (FIG. 3) have same medicinal effect, i.e. cause a 20% increase in blood pressure of the thiopental-barbital anesthetized dog. Diethylstilbestrol and the natural hormone estradiol (FIG. 4) have the same potency of estrogenic activities.
Boraadamantane compounds of this invention (FIG. 1) and amantadine (FIG. 2) are unique and new type of bioisostereomers. There are two different types of bioisosteric replacement. First, a boron atom replaces one carbon atom. Second, the covalent bond between carbon atom and nitrogen atom is replaced by a boron/nitrogen coordinate bond. In aqueous solutions, since amantadine has a pKa of 10.8, over 90% of the amino group of amantadine molecules will be protonated at physiological pH (pH 7.4). The amantadine molecules will carry a permanent positive charge while Boraadamantane compounds of this invention have a partial positive charge on the nitrogen atom and partial negative charge on boron atom. Thus they should be able to penetrate through the lipophilic cell membrane and the blood brain barrier easier than amantadine. Consequently, their anti-viral effects as well as anti-parkinsonian effects potentially will be better than amantadine. Similarity of their rigid chemical structures gives them two steric features, i.e. geometric and conformational isomerism. Thus, enhance the similarity of their pharmacological activities.
Organo-boron compounds are known to have relatively low toxicity. Carborane compounds with multiple boron atoms in the molecules have been intensely studied for boron neutron capture therapy. They have been studied for the treatment of various cancers for decades (Miura M. et al. The British Journal of Radiology, 71(1998), 773-781). Thus boraadamantane compounds of this invention which have only one boron atom per molecule should have minimum toxicity if there is any.
In summary, due to the chemical structure similarity of the Boraadamantane compounds of this invention (FIG. 1) and the known drug amantadine, the Boraadamantane compounds of this invention (FIG. 1) can be used for the treatment of various diseases caused by virus infections as well as Parkinson""s disease with little or no serious side effects. These compounds can be used alone or in combination with other pharmacological agents such as alpha-interferon, ribavirin, etc.